DESCRIPTION: (Applicant's Description) An understanding of the molecular mechanisms leading to human breast cancer development will come from insights into how the breast tissue develops normally. Such insights can be most easily obtained in the mouse breast, the development of which is governed by biochemical regulators very similar to those that operate to program human breast morphogenesis. Breast development is governed by bi-directional communication between the mammary epithelium and surrounding stroma. The present research examines three signalling pathways that appear to be essential for normal breast development and appear to be disrupted during cancer pathogenesis. First, estrogen acting through its receptor in normal mammary epithelial cells (MECs) does not appear to be mitogenic but has acquired such powers in many human breast carcinoma cells. The proposed research examines the possibility that these powers result from the inappropriate expression of a co-activator of the receptor that is not normally expressed in MECs. A second aspect of breast signalling involves the progesterone receptor, which is responsible for sidebranching of mammary ducts. The present research examines the possibility that this receptor, when activator by progesterone, causes expression of hepatocyte growth factor in nearby stroma; this factor then acts on MECs to induce ductal sidebranching. A third line of research examines the possibility that prolactin, acting through its receptor in MECs, is able to induce the production of the neuregulin growth factor in nearby stromal tissue; once released, the neuregulin causes MEC proliferation leading to the formation of alveoli. The latter pathway is often subverted in human mammary carcinoma cells that express the HER2 receptor of neuregulin.